Melatonin enhances L‐DOPA therapeutic effects, helps to reduce its dose, and protects dopaminergic neurons in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced parkinsonism in mice

Abstract

L-3,4-dihydroxyphenylalanine (L-DOPA) reduces symptoms of Parkinson's disease (PD), but suffers from serious side effects on long-term use. Melatonin (10-30 mg/kg, 6 doses at 10 hr intervals) was investigated to potentiate L-DOPA therapeutic effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in mice. Striatal tyrosine hydroxylase (TH) immunoreactivity, TH, and phosphorylated ser 40 TH (p-TH) protein levels were assayed on 7th day. Nigral TH-positive neurons stereology was conducted on serial sections 2.8 mm from bregma rostrally to 3.74 mm caudally. MPTP caused 39% and 58% decrease, respectively, in striatal fibers and TH protein levels, but 2.5-fold increase in p-TH levels. About 35% TH neurons were lost between 360 and 600 μm from 940 μm of the entire nigra analyzed, but no neurons were lost between 250 μm rostrally and 220 μm caudally. When L-DOPA in small doses (5-8 mg/kg) failed to affect MPTP-induced akinesia or catalepsy, co-administration of melatonin with L-DOPA attenuated these behaviors. Melatonin administration significantly attenuated MPTP-induced loss in striatal TH fibers (82%), TH (62%) and p-TH protein (100%) levels, and nigral neurons (87-100%). Melatonin failed to attenuate MPTP-induced striatal dopamine depletion. L-DOPA administration (5 mg/kg, once 40 min prior to sacrifice, p.o.) in MPTP- and melatonin-treated mice caused significant increase in striatal dopamine (31%), as compared to L-DOPA and MPTP-treated mice. This was equivalent to 8 mg/kg L-DOPA administration in parkinsonian mouse. Therefore, prolonged, effective use of L-DOPA in PD with lesser side effects could be achieved by treating with 60% lower doses of L-DOPA along with melatonin.

Melatonin as an antioxidant: under promises but over delivers

“…There should be long duration trials of melatonin against serious diseases (where few treatments are available) where it has been shown beneficial in limited clinical studies or where the experimental evidence is compelling. Some examples include melatonin's ability to forestall Alzheimer's disease, [301][302][303] Parkinson's disease, [304][305][306] multiple sclerosis, 307,308 osteoporosis, [309][310][311] diabetes and metabolic syndrome, 312-315 sepsis, [316][317][318] cancer, [319][320][321] tropical diseases, [322][323][324][325] snake and nematocyst venom toxicity, [326][327][328][329] etc. In some cases, rather than a treatment for these conditions, melatonin should be more strongly considered in terms of its preventative actions as prevention always trumps treatment and is usually less expensive and certainly less debilitating.…”

Pre‐ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress‐dependent autophagy via PERK and IRE1 signalings

“…Melatonin (N‐acetyl‐5‐methoxytryptamine) has demonstrated diverse pharmacological capabilities, including anti‐inflammation, antioxidative stress, anti‐apoptotic, and analgesic properties . Melatonin exerts beneficial effects in multiple central nervous conditions, including subarachnoid hemorrhage, Parkinson's disease, Alzheimer's disease, cognitive impairment, and anxiety disorders . Moreover, recent researches revealed that melatonin can protect against cerebral ischemic injury.…”

“…5,6 Melatonin exerts beneficial effects in multiple central nervous conditions, including subarachnoid hemorrhage, Parkinson's disease, Alzheimer's disease, cognitive impairment, and anxiety disorders. [7][8][9][10][11] Moreover, recent researches revealed that melatonin can protect against cerebral ischemic injury. Our report shows that melatonin modulates the SIRT1 pathway to protect mitochondrial function and prevent cell apoptosis after ischemia.…”

Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms

“…Melatonin treatment prevented the loss of TH-positive neurons in the SNc at the same time which improved motor deficits induced by MPTP [144, 151]. Furthermore, melatonin, when coadministered with L-DOPA, was able to improve the motor benefits induced by L-DOPA [157] (Table 2). …”